Can Post-Operative Posterior Reversible Encephalopathy Syndrome (PRES) Be Considered an Insidious Rare Surgical Complication?

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by neurological symptoms and distinctive neuroimaging findings. There are a few cases reported in the literature in which PRES can occur after surgery, and there is no clear direct relationship between a procedure and its debut. Methods: We performed a review of the literature by analyzing all reported cases of PRES syndrome which debuted after a surgical procedure with the aim of identifying the clinical features, the timing of the symptoms’ onset and the therapy of patients suffering from this unusual surgical complication. Results: The total number of patients collected was 47, with a mean age of 40.9 years. Postoperative PRES can occur in either pediatric or adult patients (ages 4–82 years). The most frequent form of comorbidity reported was cardiovascular disease (fourteen patients, 29.78%). Sixteen patients (36%) had no relevant risk factors or comorbidities at the time of the surgical procedure. The types of surgery most correlated were cranial neuro and maxillofacial surgery (twenty-one patients, 44.68%) followed by transplant surgery (eight patients, 17%). The time of onset of PRES after surgery occurred within the first 3 weeks (mean time of onset 4.7 days), and when rapidly treated with antihypertensive and antiepileptic drugs appeared to have a reversible and benign course. Conclusion: PRES syndrome can be considered a rare complication of procedures and can occur following a wide range of surgeries, especially cranial and transplant surgery. Being able to recognize it in time and treat it ensures a full reversibility of symptoms in most cases.


Introduction
Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder described by Hinchey in 1996 [1], characterized by a large variety of neurological signs [1][2][3][4] and distinctive neuroimaging findings reflecting vasogenic edema observed predominantly in the posterior regions of the brain [1,5,6]. The onset may be acute or subacute [6], with symptoms developing within a few hours up to several weeks [4,5,7]. Patients may present with signs of encephalopathy [8,9], epileptic seizures [4], and following the frequent involvement of the occipital lobes, visual disturbances such as a deterioration of visual acuity [1]. Less specific neurological symptoms include headache, nausea, vomiting and, depending 2 of 16 on the lesions' location, focal neurological deficits, reported in 5-15% of cases [5]. Both clinical and imaging characteristics are usually reversible [9], even if, on average, about 40% of all patients diagnosed with PRES require intensive care monitoring [8] and treatment due to severe complications such as status epilepticus, cerebral ischemia, intracranial hemorrhage or intracranial hypertension [4,10].
The pathophysiology of PRES is still controversial and unclear. It could be caused by a variety of etiologies, among which uncontrolled hypertension is regarded as the main culprit, observed in about 75% of patients [5,11]. Alterations in the hemodynamic state can lead to PRES, and acute hypertension that overcomes cerebral autoregulation leads to the breakdown of the blood-brain barrier (BBB), cerebral vasodilatation, and transudation of fluid, resulting in brain edema [12]. Because the anterior cerebral circulation is much better supplied with sympathetic innervation than the posterior circulation, the posterior cerebral circulation may be predisposed to a loss of protective vasoconstriction, breakthrough vasodilation and vasogenic edema in the face of acute hypertension [4]. Most patients are markedly hypertensive on presentation; however, some have only mildly increased or even normal blood pressure. There are a few cases reported in the literature in which PRES can occur after surgery; however, there is no clear, direct relationship between a procedure and the onset of this insidious syndrome [13]. No study in the literature identifies PRES as a complication of a surgical procedure, and it is not known whether it may be driven by surgery-related stress or mismanagement of general anesthesia during the procedure [14].
In this review, we collected all cases reported in the literature of PRES arising after surgery with the aim of identifying the causes, clinical features of onset, treatment and management of what could be a dreaded though rare postoperative complication.

Materials and Methods
We performed a review of the literature by analyzing all reported cases of PRES syndrome debuted after a surgical procedure, with the aim of identifying the clinical features, timing of symptoms' onset and therapy of patients suffering from this unusual surgical complication.

Eligibility Criteria
Our target was to identify the type of surgical procedure performed, the time of onset, clinical and time debut, and the clinical prognosis of patients who experienced symptoms attributable to PRES syndrome from the immediate postoperative stage. Therefore, while screening the literature, we adopted the following inclusion criteria: • Meta-analysis, case series, clinical study or clinical image reporting cases of patients who suffered from PRES syndrome after a surgical procedure.
Conversely, we excluded the following: • Cases reported without detailed clinical features of patients; • Cases reported without description of radiological images; • Papers that report other pathologies (off topic); • Papers written in languages other than English.
The English literature was systematically investigated using MEDLINE, the NIH Library, Pubmed and Google Scholar. The last search date was 5 May 2022. The following search terms were used: PRES syndrome AND "Post-operative" OR "after surgery".
Two independent reviewers (D.A. and F.C.) screened each record (title/abstract) and each report retrieved at each stage of screening. Duplicated articles were removed after the first investigation of the libraries.

Results
The search returned a total of 160 papers, including radiological, molecular and clinical studies. In Figure 1, the article selection flow-chart with PRISMA criteria is reported accordingly (Figure 1). To this initial cohort, the aforementioned exclusion criteria were Brain Sci. 2023, 13, 706 3 of 16 applied, accordingly eliminating a total of 10 papers for duplicated title and language selection. The resulting 150 papers were evaluated by title and abstract: 16 articles were exclude because they were outside the topic (not referring to the PRES syndrome) and 87 articles were excluded because they did not focus on clinical outcome (comprehensive review, book chapters, clinical images) or because they were not in relation to a surgical procedure. Five articles were subsequently excluded after a complete revision of the paper for incomplete data. The list of 42 evaluated articles is given in Table 1.

Results
The search returned a total of 160 papers, including radiological, molecular a ical studies. In Figure 1, the article selection flow-chart with PRISMA criteria is r accordingly (Figure 1). To this initial cohort, the aforementioned exclusion criter applied, accordingly eliminating a total of 10 papers for duplicated title and langu lection. The resulting 150 papers were evaluated by title and abstract: 16 articles w clude because they were outside the topic (not referring to the PRES syndrome) articles were excluded because they did not focus on clinical outcome (compre review, book chapters, clinical images) or because they were not in relation to a s procedure. Five articles were subsequently excluded after a complete revision of th for incomplete data. The list of 42 evaluated articles is given in Table 1. For each case described, we reported the sex and age of the patient, the pres comorbidity or risk factors, the type of surgery performed, whether there were pe ative complications, the time of clinical onset of PRES syndrome, the predominan symptomatology, the eventual time of symptom recovery, and the prognostic sta ported as "Good" if there was complete recovery of PRES symptoms, "stable" were permanent but controlled changes, "worst" if there was clinical worsening w duced expectancy or quality of life). From the time of the onset of PRES, all patien rienced symptoms of seizure states and hypertensive states and we reported "seiz the main symptom when it was the only onset symptom.
The total number of patients collected for this review was 47, with a mean age years. Postoperative PRES syndrome can occur in either pediatric or adult age p with a reported minimum age of 4 years to a maximum of 82 years. There was no c prevalence in the manifestation of the syndrome, with 25 female and 21 male indi reported (one sex data point was missing in one case report).
The patient comorbidities reported were very varied, including gastroentero renal, immune and metabolic diseases. The most frequent form of comorbidity r was cardiovascular disease (14 patients, 29.78%). Of note, however, a significant p age of patients had no relevant risk factors or comorbidities at the time of the s procedure (16 patients, 36%). For each case described, we reported the sex and age of the patient, the presence of comorbidity or risk factors, the type of surgery performed, whether there were perioperative complications, the time of clinical onset of PRES syndrome, the predominant onset symptomatology, the eventual time of symptom recovery, and the prognostic status (reported as "Good" if there was complete recovery of PRES symptoms, "stable" if there were permanent but controlled changes, "worst" if there was clinical worsening with reduced expectancy or quality of life). From the time of the onset of PRES, all patients experienced symptoms of seizure states and hypertensive states and we reported "seizure" as the main symptom when it was the only onset symptom.
The total number of patients collected for this review was 47, with a mean age of 40.9 years. Postoperative PRES syndrome can occur in either pediatric or adult age patients, with a reported minimum age of 4 years to a maximum of 82 years. There was no clear sex prevalence in the manifestation of the syndrome, with 25 female and 21 male individuals reported (one sex data point was missing in one case report).
The patient comorbidities reported were very varied, including gastroenterological, renal, immune and metabolic diseases. The most frequent form of comorbidity reported was cardiovascular disease (14 patients, 29.78%). Of note, however, a significant percentage of patients had no relevant risk factors or comorbidities at the time of the surgical procedure (16 patients, 36%). On the other hand, if we consider the type of surgery most correlated with the postoperative onset of PRES syndrome, it shows that the types of surgery most involved are cranial neuro and maxillofacial surgery (twenty-one patients, 44.68% of cases), transplant surgery (eight patients, 17%) and orthopedic and spine surgery (six patients, 12.76%), all three accounting for more than 70% of the surgeries in which this complication may occur.
In the majority of cases (39 patients, 83%), there were no intra-operative complications reported in the selected studies. The time of onset of PRES syndrome after surgery was reported in 45/47 patients, and in most cases (43 patients 91.5%) it occurred within the first 3 weeks (mean time of onset 4.7 days); in two cases, late onset was found at 6 and 10 months (in both cases, after prolonged therapy with immunosuppressive drugs, Tacrolimus). In the cases in which we have reported onset at 1 day, we refer to onset within the first 24 h after cessation of sedation after the procedure.
All reported patients experienced epileptic symptoms, where in 21 cases it was the only manifestation of the syndrome and in 19 cases (40%) there was a loss of acute visual acuity as the initial symptom. We found that even in cases of PRES arising after a surgical procedure, the symptomatology tended to be self-limiting and transient with a full recovery of neurological symptoms occurring in 35 patients (74.5%). In these cases, effective anti-hypertensive and anti-epileptic therapy was introduced at the first manifestation of symptoms.
The time to recovery of Initial neurological status was found to be widely variable, from a minimum of 2 days to a maximum of 18 months, with no apparent correlation with the type of surgery, the presence of hypertension among the risk factors, and the presence of peri-operative complications. A valid statistical analysis could not be performed due to the small number of patients reported. Resumed data are reported in Table 2.

Discussion
Although numerous case reports and observational studies have been published, the pathophysiology, treatment and prognosis of PRES has remained unclear since its first description [1,7,9,[53][54][55]. Currently, there are no diagnostic criteria or guidelines for PRES, and clinical and neuroimaging findings are often not specific [5,56,57]. There are two leading theories regarding the pathophysiology of PRES [9]: the first hypothesis, the 'vasogenic theory', proposes a rapid increase in arterial blood pressure up to a hypertensive crisis, which has been observed in most patients at PRES onset [5]. According to this hypothesis, the elevation of blood pressure levels above the upper autoregulatory limit leads to cerebral hyperperfusion [58], causing a breakdown of the BBB and secondary vasogenic edema [9,59,60]. The cerebral hemispheres' posterior areas seem particularly susceptible, supported by clinical and imaging findings [5]. However, this theory does not explain the mechanism in patients with borderline hypertension and normotensives (30% of patients with PRES [61]). The 'neuropeptide' theory regarding the cause of PRES is that the syndrome is triggered by endothelial dysfunction caused by circulating endogenous or exogenous toxins [62], causing vasospasm and ischemia and cerebral edema as a consequence of primary endothelial dysfunction, increased vascular permeability and edema formation [9,53]. Arguing for this hypothesis, PRES is frequently observed in patients with (pre)eclampsia [7], sepsis, trauma, or during treatment regimens with immunosuppressive agents [63] or cytotoxic medication [64,65]. Many authors report that a significant number of PRES cases occurred after a surgical procedure. In this research, we found that while the pathology leading up to the procedure, the therapy, and the sedation used during the procedure were hypothesized to be in relation to the onset of PRES, in fact there does not seem to be a direct correlation with one pathology versus another. We have identified cases of postoperative PRES in patients treated for gastrointestinal pathology [27,30,47], gynecologic pathology [12], and even urologic pathology [31,48]. Several anesthesiologic reports [12,27,31,50] on PRES have argued that the major causative factor could be suboptimal pressure control in hypertensive patients [25,26]. We found that the most frequent form of comorbidity reported was cardiovascular disease, effectively [44], although it is reported in a percentage less than 30%, with the majority of patients being without known risk factors. Although there are various causes of this syndrome, not all affected patients typically have a history of hypertension at the time of presentation [34,44]. Further, perioperative hypertension occurs in 25% of hypertensive patients undergoing surgery without neurological consequences [66]. With regard to the role of immunosuppressive agents, particularly calcineurin inhibitors [21] and tacrolimus [33], reported in most studies as causative, it is noteworthy that only four of our series reported high plasma levels. It is likely that the mentioned risk factors (hypertension and calcineurin inhibitors) are important but insufficient to cause PRES, and they are thought to be associated with other, still unidentified factors that influence endothelial function, BBB, or fluid homeostasis [33].
Each reported case of postoperative PRES was analyzed from the perspective of the pathology of interest, going on to hypothesize, for example, the role of primary damage to the BBB in cases of operated posterior cranial fossa lesions [15,18,46], or immunosuppressive therapy [17,20,21,39,40] in patients undergoing organ transplantation [35,52]. Instead, we believe that in individuals predisposed to have primary endothelial damage, a stressful incident such as surgery of whatever type may result in postoperative PRES in rare cases. In most cases Figure 2, no intra-operative complications were reported in the selected studies. We found that there was a higher percentage for certain types of surgery, such as in the case of neurosurgical pathology [16,24,28,29,32], both cranial and spinal [15,18,19,36,42,49]. In some cases, the risk factor for PRES was sustained by hypertension caused by incomplete postoperative pain control [67]. Adequate pain control may have prevented the development of PRES [34].
So while it is true that it is not, therefore, possible to accurately predict the real risk of developing PRES after a surgical procedure, it should also be understood that since it is a condition with self-limiting symptoms, the operator's awareness that it is a rare complication can be of profound help in knowing how to recognize it in time and manage it in the most appropriate manner. PRES is a clinical entity that may be unfamiliar to many anesthesiologists and surgeons, but they are often the first clinicians to be confronted with a patient presenting with an acute visual loss after intraoperative hypertension. As such, they should be familiar with this diagnosis. In our opinion, PRES syndrome that occurs after neurosurgical intervention is an infrequent but not rare complication with a relevant risk of not being identified or of being mistaken for a complication of direct tissue or vascular damage after a procedure.
Differentiation from acute cerebral ischemia, and prompt and vigorous treatment of exacerbating factors, such as intermittent hypertension, are important if permanent visual loss is to be avoided [12]. Brain imaging is useful to exclude alternative diagnoses, and usually confirms a PRES diagnosis [5] and suggests any sequelae like hemorrhages [68] or hydrocephalus described in our representative case [56,69]. Computed tomography (CT) scans usually show vasogenic edema with a bi-hemispheric distribution [9]. However, magnetic resonance imaging (MRI) is the most important diagnostic tool; it is more sensitive to displaying hyperintense lesions in T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences [9]. The typical MRI finding of PRES is remarkable vasogenic edema predominantly involving parieto-occipital regions (sometimes distributed asymmetrically) [70] in both hemispheres [71], with increased apparent diffusion coefficient (ADC) values (useful to determine the prognosis [72,73]) observable on diffusion-weighted imaging (DWI) [70,73,74].
However, cortical involvement has also been described [9,10]. While parieto-occipital distribution occurs in about 70% of all patients, a frontal sulcus or watershed pattern is also frequently seen [9,22,[75][76][77]. Lesions in other areas, such as the cerebellum, brain stem, basal ganglia, or spinal cord, are less common [75]. Electroencephalography (EEG) may be necessary for the detection of (non-convulsive) epileptic seizures [76,77], and status epilepticus may also help in the evaluation of encephalopathy [78][79][80][81][82]. Despite the heterogeneity in its etiologies and proposed mechanisms, PRES is a downstream effect characterized by a combination of clinical and radiological features [69].
pressive therapy [17,20,21,39,40] in patients undergoing organ transplantation [35,52]. Instead, we believe that in individuals predisposed to have primary endothelial damage, a stressful incident such as surgery of whatever type may result in postoperative PRES in rare cases. In most cases Figure 2, no intra-operative complications were reported in the selected studies. We found that there was a higher percentage for certain types of surgery, such as in the case of neurosurgical pathology [16,24,28,29,32], both cranial and spinal [15,18,19,36,42,49]. In some cases, the risk factor for PRES was sustained by hypertension caused by incomplete postoperative pain control [67]. Adequate pain control may have prevented the development of PRES [34].

Figure 2.
This is a representative case of a 55-year-old woman with no significant previous medical history and essential hypertension, who was transported to our emergency unit after the onset of right hemiplegia with Glasgow Coma Scale (GCS) 6, preceded by a severe headache which occurred two hours earlier. On initial evaluation, blood pressure was elevated at 160/100 mmHg. A head Figure 2. This is a representative case of a 55-year-old woman with no significant previous medical history and essential hypertension, who was transported to our emergency unit after the onset of right hemiplegia with Glasgow Coma Scale (GCS) 6, preceded by a severe headache which occurred two hours earlier. On initial evaluation, blood pressure was elevated at 160/100 mmHg. A head angio computed tomography (A) scan performed at our department showed a large left frontotemporal subdural hemorrhage. A left front-temporoparietal decompressive craniectomy was performed to remove the hematoma. Postoperative head CT scan (B) showed the surgical results, with complete clot removal with a significant reduction in the midline shift. The patient was therefore transferred to our intensive care unit. During sedation, the patient had poorly controlled hypertensive peaks and the causes of secondary hypertension were excluded (urinary catecholamines analysis, abdominal CT-scan and serum-level hormones). The patient was extubated four days after the craniectomy. The neurological examination documented a slight improvement in the right side motor disorder and a considerable improvement in the consciousness state, with a GCS 10. A brain MRI (C) was performed about 3 weeks after surgery, which showed bilateral occipital, parietal and left frontal cortex and subcortical white matter T2/Fluid-attenuated inversion recovery (FLAIR) hyperintensities associated with disruption of the BBB evident after administration of gadolinium, suggestive of PRES. The patient underwent a cranioplasty with her autologous bone flap after three weeks. On follow-up at six weeks, the patient did not present modification of neurological status and reported no recurrence of severe neurological deficits or seizures. She was submitted to an Electroencephalography (EEG) that showed normal, reduced electroencephalographic activity without sign of seizure, and a follow-up head CT scan showed an enlargement of the frontal ventricles (D), and the patient was given third ventriculostomy and a ventriculoperitoneal shunt. After one week, the patient showed a general improvement in verbal and motor response.
The treatment of PRES is symptomatic since no specific therapeutic strategy is currently available. Early recognition is crucial, as timely management of its precipitating factor is required to achieve reversibility [4]. No guidelines exist to direct this assessment; therefore, clinical judgment is crucial since PRES diagnosis is not mainly radiological [43]; the clinical context and clinician's judgment are essential to making the correct diagnosis [5]. Every patient in this series, during or after the onset of neurological symptoms, presented a state of hypertension. Although no randomized control trials have been held to assess the effect of blood pressure management on PRES resolution, the consensus among physicians suggests that the control of hypertensive episodes and normal blood pressure maintenance is an essential component of treatment [5,72,83]. An early indication of PRES could lead to timely [51], appropriate management of this potentially reversible and treatable disorder, resulting in positive clinical outcomes. Anticonvulsive treatment is frequently required. There Is no general recommendation for the use of specific drugs [72], and specific prognostic factors have not been identified. Although PRES-associated clinical signs and symptoms and neuroimaging lesions are reversible in the majority of patients, the prognosis is mainly determined by the underlying pathology [23,38,41,45,84,85] and the following treatment, considering that possible neurological sequelae, in particular, reduced visual acuity and epilepsy, may persist in individual cases. Large, multi-center prospective studies using inclusive diagnostic criteria would be valuable to examine associations with surgery, atypical manifestations and prognosis.

Conclusions
PRES is a complex and difficult to recognize neurological syndrome probably caused by an intrinsic endothelial defect that may arise following several stressogenic insults including a surgical procedure. Recognizing PRES as a surgical complication allows its rapid diagnosis and management while achieving good clinical outcomes.  Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient(s) to publish this paper. Data Availability Statement: Not applicable.

Conflicts of Interest:
The authors declare no conflict of interest.